Study of SHP620 (Maribavir) in Healthy Adults

NCT02775240 | Completed Phase 1 Results

• 1 other identifier: SHP620-115
• Study Type: interventional
• Target: 18
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this study is to determine how an investigational treatment (maribavir) is handled by the body when administered with two already approved drugs (digoxin and dextromethorphan). The study will also look at the safety and tolerability when maribavir is coadministered with digoxin and dextromethorphan versus digoxin and dextromethorphan alone.

Conditions

Cytomegalovirus (CMV)

Keywords

Maribavir

Outcome Measures

Primary Outcomes (31)

• Maximum Observed Plasma Concentration (Cmax) of Digoxin

  Cmax is the maximum observed plasma concentration of digoxin.

  Pre-dose,0.25,0.5,1,1.5,2,3,4,5,6,8,12,24,48,72 hours post-dose on Day 1 for Treatment A and Day 13 for Treatment B

• Maximum Observed Plasma Concentration (Cmax) of Dextromethorphan

  Cmax is the maximum observed plasma concentration of dextromethorphan.

  Pre-dose,0.25,0.5,1,1.5,2,3,4,5,6,8,12,24,48,72 hours post-dose on Day 1 for Treatment A and Day 13 for Treatment B

• Maximum Observed Plasma Concentration (Cmax) of Dextrorphan

  Cmax is the maximum observed plasma concentration of dextrorphan, the metabolite of dextromethorphan.

  Pre-dose,0.25,0.5,1,1.5,2,3,4,5,6,8,12,24,48,72 hours post-dose on Day 1 for Treatment A and Day 13 for Treatment B

• Maximum Observed Plasma Concentration (Cmax) of Maribavir

  Cmax is the maximum observed plasma concentration of maribavir.

  Pre-dose, 0.25,0.5,1,1.5,2,3,4,5,6,8,12 hours post-dose on Day 13

• Time to Reach Maximum Plasma Concentration (Tmax) of Digoxin

  Tmax is the time to reach the maximum observed drug concentration in plasma during a dosing interval.

  Pre-dose,0.25,0.5,1,1.5,2,3,4,5,6,8,12,24,48,72 hours post-dose on Day 1 for Treatment A and Day 13 for Treatment B

• Time to Reach Maximum Plasma Concentration (Tmax) of Dextromethorphan

  Tmax is the time to reach the maximum observed drug concentration in plasma during a dosing interval.

  Pre-dose,0.25,0.5,1,1.5,2,3,4,5,6,8,12,24,48,72 hours post-dose on Day 1 for Treatment A and Day 13 for Treatment B

• Time to Reach Maximum Plasma Concentration (Tmax) of Dextrorphan

  Tmax is the time to reach the maximum observed drug concentration in plasma during a dosing interval.

  Pre-dose,0.25,0.5,1,1.5,2,3,4,5,6,8,12,24,48,72 hours post-dose on Day 1 for Treatment A and Day 13 for Treatment B

• Time to Reach Maximum Plasma Concentration (Tmax) of Maribavir

  Tmax is the time to reach the maximum observed drug concentration in plasma during a dosing interval.

  Pre-dose, 0.25,0.5,1,1.5,2,3,4,5,6,8,12 hours post-dose on Day 13

• Area Under the Plasma Concentration Versus Time Curve Extrapolated to Infinity (AUC0-infinity) of Digoxin

  AUC0-infinity is the area under the plasma concentration versus time curve extrapolated to infinity, calculated using the observed value of the last non-zero concentration.

  Pre-dose,0.25,0.5,1,1.5,2,3,4,5,6,8,12,24,48,72 hours post-dose on Day 1 for Treatment A and Day 13 for Treatment B

• Area Under the Plasma Concentration Versus Time Curve Extrapolated to Infinity (AUC0-infinity) of Dextromethorphan

  AUC0-infinity is the area under the plasma concentration versus time curve extrapolated to infinity, calculated using the observed value of the last non-zero concentration.

  Pre-dose,0.25,0.5,1,1.5,2,3,4,5,6,8,12,24,48,72 hours post-dose on Day 1 for Treatment A and Day 13 for Treatment B

• Area Under the Plasma Concentration Versus Time Curve Extrapolated to Infinity (AUC0-infinity) of Dextrorphan

  AUC0-infinity is the area under the plasma concentration versus time curve extrapolated to infinity, calculated using the observed value of the last non-zero concentration.

  Pre-dose,0.25,0.5,1,1.5,2,3,4,5,6,8,12,24,48,72 hours post-dose on Day 1 for Treatment A and Day 13 for Treatment B

• Area Under the Plasma Concentration Versus Time Curve From the Time of Dosing to the Last Measurable Concentration (AUClast) of Digoxin

  AUClast is the area under the plasma concentration versus time curve from the time of dosing to the last measurable concentration.

  Pre-dose,0.25,0.5,1,1.5,2,3,4,5,6,8,12,24,48,72 hours post-dose on Day 1 for Treatment A and Day 13 for Treatment B

• Area Under the Plasma Concentration Versus Time Curve From the Time of Dosing to the Last Measurable Concentration (AUClast) of Dextromethorphan

  AUClast is the area under the plasma concentration versus time curve from the time of dosing to the last measurable concentration.

  Pre-dose,0.25,0.5,1,1.5,2,3,4,5,6,8,12,24,48,72 hours post-dose on Day 1 for Treatment A and Day 13 for Treatment B

• Area Under the Plasma Concentration Versus Time Curve From the Time of Dosing to the Last Measurable Concentration (AUClast) of Dextrorphan

  AUClast is the area under the plasma concentration versus time curve from the time of dosing to the last measurable concentration.

  Pre-dose,0.25,0.5,1,1.5,2,3,4,5,6,8,12,24,48,72 hours post-dose on Day 1 for Treatment A and Day 13 for Treatment B

• Parent/Metabolite Ratio of Area Under the Plasma Concentration Versus Time Curve From the Time of Dosing to the Last Measurable Concentration (AUClast) for Dextromethorphan Over AUClast for Dextrorphan (AUClast Parent/Metabolite Ratio)

  AUClast parent/metabolite ratio is the ratio of AUClast for dextromethorphan over AUClast for dextrorphan.

  Pre-dose,0.25,0.5,1,1.5,2,3,4,5,6,8,12,24,48,72 hours post-dose on Day 1 for Treatment A and Day 13 for Treatment B

• Parent/Metabolite Ratio of Area Under the Plasma Concentration Versus Time Curve Extrapolated to Infinity (AUC0-infinity) for Dextromethorphan Over AUC0-infinity for Dextrorphan (AUC0-infinity Parent/Metabolite Ratio)

  AUC0-infinity parent/metabolite ratio is the ratio of AUC0-infinity for dextromethorphan over AUC0-infinity for dextrorphan.

  Pre-dose,0.25,0.5,1,1.5,2,3,4,5,6,8,12,24,48,72 hours post-dose on Day 1 for Treatment A and Day 13 for Treatment B

• Area Under the Plasma Concentration Versus Time Curve From Time Zero to the End of the Dosing Interval at Steady-State (AUCtau) of Maribavir

  AUCtau is the area under the plasma concentration versus time curve from the time zero to the end of the dosing interval at steady-state.

  Pre-dose, 0.25,0.5,1,1.5,2,3,4,5,6,8,12 hours post-dose on Day 13

• First-order Rate Constant (Lambda z) Associated With the Terminal (Log-linear) Portion of the Curve of Digoxin

  Lambda z is the first-order rate constant associated with the terminal (log-linear) portion of the plasma concentration versus time curve, determined as the negative slope of the terminal log-linear phase of the curve.

  Pre-dose,0.25,0.5,1,1.5,2,3,4,5,6,8,12,24,48,72 hours post-dose on Day 1 for Treatment A and Day 13 for Treatment B

• First-order Rate Constant (Lambda z) Associated With the Terminal (Log-linear) Portion of the Curve of Dextromethorphan

  Lambda z is the first-order rate constant associated with the terminal (log-linear) portion of the plasma concentration versus time curve, determined as the negative slope of the terminal log-linear phase of the curve.

  Pre-dose,0.25,0.5,1,1.5,2,3,4,5,6,8,12,24,48,72 hours post-dose on Day 1 for Treatment A and Day 13 for Treatment B

• First-order Rate Constant (Lambda z) Associated With the Terminal (Log-linear) Portion of the Curve of Dextrorphan

  Lambda z is the first-order rate constant associated with the terminal (log-linear) portion of the plasma concentration versus time curve, determined as the negative slope of the terminal log-linear phase of the curve.

  Pre-dose,0.25,0.5,1,1.5,2,3,4,5,6,8,12,24,48,72 hours post-dose on Day 1 for Treatment A and Day 13 for Treatment B

• Terminal Half-life (t1/2) of Digoxin

  Terminal half-life (t1/2) is the time in hours required for the concentration of the drug to reach half of its original value.

  Pre-dose,0.25,0.5,1,1.5,2,3,4,5,6,8,12,24,48,72 hours post-dose on Day 1 for Treatment A and Day 13 for Treatment B

• Terminal Half-life (t1/2) of Dextromethorphan

  Terminal half-life (t1/2) is the time in hours required for the concentration of the drug to reach half of its original value.

  Pre-dose,0.25,0.5,1,1.5,2,3,4,5,6,8,12,24,48,72 hours post-dose on Day 1 for Treatment A and Day 13 for Treatment B

• Terminal Half-life (t1/2) of Dextrorphan

  Terminal half-life (t1/2) is the time in hours required for the concentration of the drug to reach half of its original value.

  Pre-dose,0.25,0.5,1,1.5,2,3,4,5,6,8,12,24,48,72 hours post-dose on Day 1 for Treatment A and Day 13 for Treatment B

• Terminal Half-life (t1/2) of Maribavir

  Terminal half-life (t1/2) is the time in hours required for the concentration of the drug to reach half of its original value.

  Pre-dose, 0.25,0.5,1,1.5,2,3,4,5,6,8,12 hours post-dose on Day 13

• Apparent Oral Clearance (CL/F) of Digoxin

  CL/F is equal to dose/AUC0-infinity (dose divided by area under the plasma concentration versus time curve extrapolated to infinity \[AUC0-infinity\]).

  Pre-dose,0.25,0.5,1,1.5,2,3,4,5,6,8,12,24,48,72 hours post-dose on Day 1 for Treatment A and Day 13 for Treatment B

• Apparent Oral Clearance (CL/F) of Dextromethorphan

  CL/F is equal to dose/AUC0-infinity (dose divided by area under the plasma concentration versus time curve extrapolated to infinity \[AUC0-infinity\])

  Pre-dose,0.25,0.5,1,1.5,2,3,4,5,6,8,12,24,48,72 hours post-dose on Day 1 for Treatment A and Day 13 for Treatment B

• Apparent Oral Clearance (CL/F) of Maribavir

  CL/F is equal to dose/AUCtau (dose divided by area under the curve from time 0 to the end of the dosing interval at steady state \[AUCtau\])

  Pre-dose, 0.25,0.5,1,1.5,2,3,4,5,6,8,12 hours post-dose on Day 13

• Concentration at the End of Dosing Interval (Ctau) of Maribavir

  Ctau is the concentration of maribavir at the end of the dosing interval.

  Pre-dose, 0.25,0.5,1,1.5,2,3,4,5,6,8,12 hours post-dose on Day 13

• Volume of Distribution Divided by the Fraction of Dose Absorbed (Vz/F) of Digoxin

  Vz/F is the volume of distribution associated with the terminal slope following extravascular administration divided by the fraction of dose absorbed.

  Pre-dose,0.25,0.5,1,1.5,2,3,4,5,6,8,12,24,48,72 hours post-dose on Day 1 for Treatment A and Day 13 for Treatment B

• Volume of Distribution Divided by the Fraction of Dose Absorbed (Vz/F) of Dextromethorphan

  Vz/F is the volume of distribution associated with the terminal slope following extravascular administration divided by the fraction of dose absorbed.

  Pre-dose,0.25,0.5,1,1.5,2,3,4,5,6,8,12,24,48,72 hours post-dose on Day 1 for Treatment A and Day 13 for Treatment B

• Pre-dose Concentration (C0) of Maribavir

  C0 is the lowest concentration reached by a drug before the next dose is administered.

  Pre-dose on Day 13

Secondary Outcomes (2)

• Number of Participants With Study-related Adverse Events (AEs), Serious Adverse Events (SAEs) and Treatment-emergent Adverse Events (TEAEs)

  From start of study drug administration up to follow-up (up to 25 days)

• Number of Participants With Clinically Significant Changes Reported as TEAE in Physical Examination, Vital Signs, 12-lead ECGs, Hematology, Blood Chemistry and Urinalysis

  Baseline up to Day 16

Study Arms (3)

Digoxin

ACTIVE COMPARATOR

On Day 1, subjects will receive a single 0.5 mg (2 x 0.25 mg) oral dose of digoxin.

Drug: Digoxin

Maribavir

EXPERIMENTAL

On Day 8 through Day 15, subjects will receive a 400 mg (2 x 200 mg) BID oral dose of maribavir. Subjects will be given the second dose of maribavir approximately 12 hours after the first dose. On Day 13, subjects will receive a coadministration of a single 0.5 mg (2 x 0.25 mg) oral dose of digoxin and a single 30 mg oral dose of dextromethorphan given with the morning dose of maribavir.

Drug: Digoxin; Drug: Maribavir; Drug: Dextromethorphan

Dextromethorphan

ACTIVE COMPARATOR

On Day 1, subjects will receive a single 30 mg oral dose of dextromethorphan.

Drug: Dextromethorphan

Interventions

Digoxin DRUG

0.5 mg (2 x 0.25 mg) Digoxin oral dose

Digoxin; Maribavir

Maribavir DRUG

200mg twice a day for 8 days

Maribavir

Dextromethorphan DRUG

30 mg oral dose

Dextromethorphan; Maribavir

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• An understanding, ability, and willingness to fully comply with study procedures and restrictions.
• Ability to provide written, personally signed, and dated informed consent to participate in the study, before completing any study-related procedures.
• Age 18-50 years, inclusive at the time of consent.
• Subjects must be willing to consent to and provide blood samples for pharmacogenomics analysis.
• Willingness to comply with any applicable contraceptive requirements of the protocol and is:
• Male, or
• Female of non-childbearing potential
• Non-pregnant, non-lactating female
• Females must be at least 90 days postpartum or nulliparous.
• Must be considered "healthy." Healthy status is defined by absence of evidence of any active or chronic disease following a detailed medical and surgical history, a complete physical examination including vital signs, 12-lead ECG, hematology, blood chemistry (includes T3, T4, and TSH at screening only), and urinalysis.
• Body mass index (BMI) between 18.5 and 30.0 kg/m2 inclusive.
• Hemoglobin is equal to or greater than 12.0g/dL.
• Ability to swallow a dose of investigational product (which may be multiple tablets at one time or consecutively 1 tablet at a time)

You may not qualify if:

• Subject has a clinically significant history or a disorder detected during the medical interview/physical examination such as any cardiovascular, broncho-pulmonary, gastrointestinal (eg, inflammatory bowel disease, chronic diarrhea), hepatic, biliary (including gallbladder removal), renal, hematological, endocrine, autoimmune, neurological, or psychiatric disease (including depression) or any other medical condition that is capable of altering the absorption, metabolism, or elimination of drugs; or of constituting a risk factor when taking the investigational product in the judgment of the investigator.
• Known or suspected intolerance or hypersensitivity to the investigational product(s), closely related compounds, or any of the stated ingredients.
• Significant illness, as judged by the investigator, within 2 weeks of the first dose of investigational product.
• Known history of alcohol or other substance abuse within the last year.
• Donation of blood or blood products (eg, plasma or platelets) within 60 days prior to receiving the first dose of investigational product.
• Within 30 days prior to the first dose of investigational product:
• Have used an investigational product (if elimination half-life is \<6 days, otherwise 5 half-lives).
• Have been enrolled in a clinical study (including vaccine studies) that, in the investigator's opinion, may impact this study.
• Have had any substantial changes in eating habits, as assessed by the investigator.
• Confirmed systolic blood pressure \>139 mmHg or \<89 mmHg and diastolic blood pressure \>89 mmHg or \<49 mmHg.
• Twelve-lead ECG demonstrating QTcB \>450 msec at screening.
• A positive screen for alcohol or drugs of abuse at screening or Day -1, Period 1.
• Male subjects who consume more than 21 units of alcohol per week or 3 units per day; female subjects who consume more than 14 units of alcohol per week or 2 units per day (1 alcohol unit=1 beer or 1 wine \[5 oz/150 mL\] or 1 liquor \[1.5 oz/40 mL\] or 0.75 oz alcohol).
• A positive human immunodeficiency virus, hepatitis B surface antibody, or hepatitis C virus antibody screen.
• Use of tobacco in any form (eg, smoking or chewing) or other nicotine-containing products in any form (eg, gum, patch). Ex-users must report that they have stopped using tobacco for at least 30 days prior to receiving the first dose of investigational product.

Sponsors & Collaborators

• Shire: lead

Study Sites (1)

Clinical Pharmacology of Miami, Inc.

Miami, Florida, 33014, United States

Location

Related Publications (1)

• Song IH, Ilic K, Murphy J, Lasseter K, Martin P. Effects of Maribavir on P-Glycoprotein and CYP2D6 in Healthy Volunteers. J Clin Pharmacol. 2020 Jan;60(1):96-106. doi: 10.1002/jcph.1504. Epub 2019 Aug 6.

  PMID: 31385617 DERIVED

MeSH Terms

Interventions

Digoxin; maribavir; Dextromethorphan

Intervention Hierarchy (Ancestors)

Digitalis Glycosides; Cardenolides; Cardiac Glycosides; Cardanolides; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Glycosides; Carbohydrates; Morphinans; Opiate Alkaloids; Alkaloids; Heterocyclic Compounds; Heterocyclic Compounds, Bridged-Ring; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Phenanthrenes; Polycyclic Aromatic Hydrocarbons

Results Point of Contact

• Title: Study Director
• Organization: Shire

ClinicalTransparency@shire.com

+1 866 842 5335

Study Officials

• Study Director

  Takeda

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 20, 2016
• First Posted: May 17, 2016
• Study Start: July 21, 2016
• Primary Completion: September 12, 2016
• Study Completion: September 12, 2016
• Last Updated: June 3, 2021
• Results First Posted: January 16, 2019

Record last verified: 2021-05

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Access Criteria: IPD from eligible studies will be shared with qualified researchers according to the criteria and process described on https://vivli.org/ourmember/takeda/. For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.

Locations

US (1)